Hepatitis C Virus (HCV) is an enigma because it is recognized by both the cellular and humoral compartments of the immune system, yet it persists in at least 85% of those infected. Clearly, there must exist an immune deregulation of the response to HCV. We think that under host immune selection, there is an accumulation of HCV quasi species expressing functionally tolergenic epitopes conducive to viral persistence. We further postulate that as apart of the evolutionary process by which such functionally tolergenic epitopes are selected, helper T-cell responses shift towards a Th2 phenotype favoring chronic infection and creating a tolerogenic bias that specifically dampers effective anti-HCV responded even to wild-type virus. The aims of this proposal are: 1) to establish a frequency hierarchy for clones recognizing Th1 epitopes in the NS3 antigen, a protein critical to HCV infection and replication. 2) to determine the mechanism of IL-2 suppression in response to an immunodominant epitope within the nine-structural (NS) 3 protein antigen of HCV. 3) to examine the relationship between viral nutation and functionally distinct helper T-cell epitopes that stimulate production of different cytokines. 4) to define the location and cytokine profiles of functionally distinct epitopes found in the nucleocapsid or Core protein antigen of HCV. We believe that understanding the structural constraints upon helper T-cell interactions with functionally distinct HCV epitopes provides a powerful vantage point from which to study immune regulation in humans and may lead to strategies for interviewing in the infectious process. Our studies are designed to test some of the in vitro correlates of this hypothesis and to gain insights into how natural variations in viral epitopes can lead to modulation of human T-cell responses. An understanding of this process is likely to bear on mechanisms and consequences of immune recognition as well as avenues of anti-viral therapeutic intervention. As we strive to address a number of important questions concerning HCV mutation and its effects on immune function, we postulate that this probably involves division of immune responses towards a Th2 or tolerogenic phenotype.